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ARTHRITIS & RHEUMATISM
Vol. 50, No. 5, May 2004, pp 1400–1411
DOI 10.1002/art.20217
© 2004, American College of Rheumatology
Radiographic, Clinical, and Functional Outcomes of Treatment
With Adalimumab (a Human Anti–Tumor Necrosis Factor
Monoclonal Antibody) in Patients With Active Rheumatoid
Arthritis Receiving Concomitant Methotrexate Therapy
A Randomized, Placebo-Controlled, 52-Week Trial
Edward C. Keystone,1 Arthur F. Kavanaugh,2 John T. Sharp,3 Hyman Tannenbaum,4 Ye Hua,5
Leah S. Teoh,5 Steven A. Fischkoff,5 and Elliot K. Chartash5
response at week 24 (improvements of at least 20% in
the American College of Rheumatology core criteria
[ACR20]), and physical function at week 52 (disability
index of the Health Assessment Questionnaire [HAQ]).
Results. At week 52, there was statistically significantly less radiographic progression, as measured by
the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean ⴞ SD
change 0.1 ⴞ 4.8) or 20 mg weekly (0.8 ⴞ 4.9) as
compared with that in the placebo group (2.7 ⴞ 6.8)
(P < 0.001 for each comparison). In addition, there were
statistically significant changes in the components of
the TSS. At week 24, ACR20 responses were achieved by
63% and 61% of patients in the adalimumab 40 mg every
other week and 20 mg weekly groups, respectively,
versus 30% of patients in the placebo group (P < 0.001
for each comparison). At week 52, ACR20 responses
were achieved by 59% and 55% of patients taking
adalimumab 40 mg every other week and 20 mg weekly,
respectively, versus 24% of patients taking placebo (P <
0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically
significant improvement with adalimumab 40 mg every
other week and 20 mg weekly compared with placebo
(mean change in HAQ score ⴚ0.59 and ⴚ0.61, respectively, versus ⴚ0.25; P < 0.001 for each comparison). A
total of 467 patients (75.4%) completed 52 weeks of
treatment. Adalimumab was generally well tolerated.
Discontinuations occurred in 22.0% of adalimumabtreated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and
nonserious) was comparable in the adalimumab and
Objective. Tumor necrosis factor (TNF) is an
important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation
in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti–TNF monoclonal
antibody, to inhibit the progression of structural joint
damage, reduce the signs and symptoms, and improve
physical function in patients with active RA receiving
concomitant treatment with methotrexate (MTX).
Methods. In this multicenter, 52-week, doubleblind, placebo-controlled study, 619 patients with active
RA who had an inadequate response to MTX were
randomized to receive adalimumab 40 mg subcutaneously every other week (n ⴝ 207), adalimumab 20 mg
subcutaneously every week (n ⴝ 212), or placebo (n ⴝ
200) plus concomitant MTX. The primary efficacy end
points were radiographic progression at week 52 (total
Sharp score by a modified method [TSS]), clinical
Supported by Abbott Laboratories, Abbott Park, Illinois.
1
Edward C. Keystone, MD: University of Toronto, Toronto,
Ontario, Canada; 2Arthur F. Kavanaugh, MD: University of California, San Diego; 3John T. Sharp, MD: University of Washington School
of Medicine, Seattle; 4Hyman Tannenbaum, MD: McGill University,
Montreal, Quebec, Canada; 5Ye Hua, MD, Leah S. Teoh, MA, Steven
A. Fischkoff, MD, Elliot K. Chartash, MD: Abbott Laboratories,
Parsippany, New Jersey.
Drs. Keystone and Kavanaugh have served as consultants to
Abbott Laboratories. Drs. Hua, Fischkoff, and Chartash own stock in
Abbott Laboratories.
Address correspondence and reprint requests to Edward C.
Keystone, MD, Mount Sinai Hospital, The Rebecca MacDonald
Centre, 2nd Floor, Room 2-006, 60 Murray Street, Toronto, Ontario
M5G 1X5, Canada.
Submitted for publication April 17, 2003; accepted in revised
form January 29, 2004.
1400
TREATMENT WITH ADALIMUMAB IN ACTIVE RA
placebo groups, although the proportion of patients
reporting serious infections was higher in patients
receiving adalimumab (3.8%) than in those receiving
placebo (0.5%) (P < 0.02), and was highest in the
patients receiving 40 mg every other week.
Conclusion. In this 52-week trial, adalimumab
was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs
and symptoms, and improving physical function in
patients with active RA who had demonstrated an
incomplete response to MTX.
Rheumatoid arthritis (RA) is an autoimmune
disease that is characterized by a progressive inflammatory synovitis of the joints which may result in erosion of
articular cartilage and subchondral bone (1). Irreversible
joint destruction frequently begins within the first year
after disease onset (1), and 70% of patients exhibit
radiographic disease progression after 2 years (2). Methotrexate (MTX), currently the standard traditional
disease-modifying antirheumatic drug (DMARD) for
RA, has been shown to improve the signs and symptoms
of RA, as well as slow the progression of joint destruction in some patients (3). However, many patients fail to
achieve an adequate or sustained response to MTX
therapy. Consequently, MTX is often combined with
other traditional DMARDs to improve outcomes.
Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in mediation of the
inflammatory synovitis, articular matrix degradation,
and bony erosions in RA and is an important molecular
target for directed biologic intervention (4). Adalimumab (Humira; Abbott Laboratories, Parsippany, NJ),
a biologic DMARD developed through phage-display
biotechnology, is the first human (100% human peptide
sequences) anti-TNF monoclonal antibody to be investigated for the treatment of RA (5–9). Structurally and
functionally analogous to naturally occurring human
IgG1, adalimumab has a terminal half-life comparable
with that of human IgG1 (⬃14 days) and demonstrates a
high specificity and affinity for TNF (Kd ⫽ 6 ⫻ 10⫺10
M). It does not bind other cytokines such as lymphotoxin. Adalimumab exerts its therapeutic effects by
blocking the interaction of TNF with the p55 and p75
TNF cell surface receptors (5). Preliminary clinical trials
have shown that adalimumab controls the signs and
symptoms of RA (6–9) and has a positive effect on the
long-term radiographic outcome (8).
The objective of this 52-week, double-blind,
placebo-controlled study was to investigate whether the
addition of adalimumab to a continuing regimen of
1401
MTX would provide additional radiographic, clinical,
and functional benefits to patients who had active RA
and had an incomplete response to MTX.
PATIENTS AND METHODS
Patients. Eligible patients were 18 years of age or
older, had active RA diagnosed according to the 1987 revised
American College of Rheumatology (ACR; formerly, American Rheumatism Association) criteria (10), and had ⱖ9 tender
joints (of 68 evaluated), ⱖ6 swollen joints (of 66 evaluated), a
C-reactive protein concentration ⬎1 mg/dl, and either rheumatoid factor positivity or at least 1 joint erosion on radiographs of the hands and feet. Patients were required to have
been on MTX therapy for ⱖ3 months at a stable dose of
12.5–25 mg/week (or ⱖ10 mg/week in patients intolerant to
MTX) for ⱖ4 weeks. Major exclusion criteria consisted of
prior use of anti-CD4 antibody therapy or TNF antagonists, a
history of an active inflammatory arthritide other than RA, a
history of active listeriosis or mycobacterial infection, a history
of lymphoma or leukemia or other malignancy besides nonmelanoma skin cancer within 5 years, a major episode of
infection (i.e., infections requiring hospitalization, treatment
with intravenous antibiotics within 30 days prior to screening,
or oral antibiotics within 14 days prior to screening), any
uncontrolled medical condition, and pregnancy or breastfeeding.
Protocol. This 52-week, double-blind, parallel-group,
placebo-controlled study was conducted at 89 sites in the
United States and Canada. The institutional review board or
research committee at each site approved the protocol, and
patients gave their written informed consent. Tuberculin skin
testing (using purified protein derivative [PPD]) was performed and standard chest radiographs were obtained prior to
the baseline visit; patients with positivity for PPD were treated
according to local recommendations.
Patients were randomly assigned to receive single
self-injections (1.6 ml/injection) of adalimumab subcutaneously at 40 mg every other week (with placebo injections on
alternate weeks), adalimumab subcutaneously at 20 mg every
week, or placebo subcutaneously every week. The dosages
used in this study were chosen to confirm the findings of an
earlier phase II 3-month dose-finding study (11) that demonstrated the efficacy of weekly subcutaneous injections of
adalimumab at 20 mg, 40 mg, and 80 mg doses. Results from
this phase II study did not show an adalimumab dose of 80 mg
to be superior to 40 mg. Furthermore, the half-life of adalimumab provided the rationale for the comparison of weekly
dosing with every other week dosing. Patients who completed
this study were eligible for an additional 52 weeks of openlabel adalimumab treatment.
Traditional DMARDs other than MTX were discontinued at least 28 days prior to the study baseline. Doses and
routes of administration of concomitant RA therapies, such as
MTX, corticosteroids, and nonsteroidal antiinflammatory
drugs (NSAIDs), were kept constant throughout the study.
Oral corticosteroids, if used previously, were allowed at a
maximum prednisone-dose equivalent of 10 mg/day. At week
16 or thereafter, patients who were not achieving an ACR20
response (improvements of at least 20% in the ACR core
1402
criteria) were allowed to receive “rescue” treatment with a
traditional DMARD at the discretion of their treating physician. Patients commencing other therapies after not achieving
an ACR20 response were considered treatment failures for the
purposes of clinical efficacy (determined by the ACR score for
level of improvement) from that time onward. Patients who
received rescue therapy and continued in the study were
included in the radiographic analysis. After week 24, patients
achieving an ACR20 response on 2 consecutive visits were
permitted dose reductions in corticosteroids (as much as 1 mg
of prednisone-dose equivalent every 2 weeks) or NSAIDs.
Increases in corticosteroid doses were not permitted. One
intraarticular corticosteroid injection was allowed between
baseline and week 16, and 2 intraarticular corticosteroid
injections were allowed between weeks 24 and 44.
Radiographic assessment. Posteroanterior radiographs of the hands/wrists and anteroposterior radiographs of
the feet were performed at screening and at weeks 24 and 52,
or at the last visit for patients who terminated participation in
the study prior to week 52. Missing radiograph values at week
52 were imputed via linear extrapolation using data collected
at baseline and week 24 or at the early-termination visit.
Radiographs were assessed using a modified version of
the Sharp method (12–14). Digitized images were scored by 2
physicians who were blinded to the treatment, chronologic
order, and clinical response of each patient. Erosion scores
were recorded for each hand/wrist (17 joints) and each forefoot (6 joints) on a 6-point scale (0 ⫽ no erosions; 1 ⫽ 1
discrete erosion or ⱕ20% joint involvement; 2 ⫽ 2 separate
quadrants with erosion or 21–40% joint involvement; 3 ⫽ 3
separate quadrants with erosion or 41–60% joint involvement;
4 ⫽ all 4 quadrants with erosion or 61–80% joint involvement;
and 5 ⫽ extensive destruction with ⬎80% joint involvement).
Joint space narrowing scores were recorded for each hand/
wrist (16 joints) and each forefoot (5 joints) on a 5-point scale
(0 ⫽ no narrowing; 1 ⫽ up to 25% narrowing; 2 ⫽ 26–65%
narrowing; 3 ⫽ 66–99% narrowing; and 4 ⫽ complete narrowing). To determine the modified total Sharp score for each
patient, the total erosion score (scale 0–230) and the joint
space narrowing score (scale 0–168) were added (total Sharp
score scale 0–398).
Clinical assessment. ACR20 responses as well as responses according to the 50% and 70% improvement levels
(ACR50 and ACR70, respectively) (15) were assessed at weeks
2 and 4, every 4 weeks from week 4 to week 24, every 8 weeks
from week 24 to week 48, and a final time at week 52. The
ACR20 response at week 24 was the primary end point, and
patients who did not achieve an ACR20 response, who withdrew from the study, or who received additional traditional
DMARD therapy on or after week 16 were classified as
nonresponders.
Physical function and health-related quality of life
assessments. Physical function was assessed at baseline and at
each visit using the disability index of the Health Assessment
Questionnaire (HAQ) (16). Health-related quality of life was
assessed at baseline and at weeks 12, 24, and 52 using the
Medical Outcomes Study 36-item Short Form health survey
(SF-36) (17).
Safety assessment. Safety was assessed through recording of adverse events, physical examinations, and standard
laboratory tests. At baseline and at weeks 24 and 52, serum
KEYSTONE ET AL
titers of antinuclear antibodies (ANAs) (positive titer ⱖ1:80)
and anti–double-stranded DNA (anti-dsDNA) antibodies
(positive titer ⬎3.5 IU/ml, determined only if ANAs were
elevated from baseline) were established by immunofluorescence on Hep-2 cells and by Farr radioimmunoassay, respectively. At baseline and at weeks 24 and 52, serum titers of
anti-adalimumab antibodies (positive titer ⬎20 ng/ml and not
suppressed by ⱖ50% after the addition of human serum) were
determined by a double-antigen immunoassay (9).
Statistical analysis. The power calculation was based
on both the predicted ACR20 response rate and radiographic
findings. A sample size of 200 patients per treatment group was
estimated to provide ⬎95% power for detecting a difference of
ⱖ20% in ACR20 response rates at week 24 between the
placebo group and the adalimumab groups at a significance
level of ␣ ⫽ 0.05, assuming a placebo response rate of 35%.
Assuming that 70% of patients would have evaluable radiograph films at 12 months, a sample size of 140 patients per
treatment group was estimated to provide 90% power for
detecting a difference in the mean increase in the modified
total Sharp scores at a significance level of ␣ ⫽ 0.05, assuming
a mean change of 2.0 in the placebo group, 0.5 in each
adalimumab group, and a pooled standard deviation of 4.0.
The study, however, was not powered to distinguish differences
between adalimumab groups.
Demographic and baseline clinical characteristics were
analyzed by Kruskal-Wallis test for continuous variables and
Pearson’s chi-square test for discrete variables. An intent-totreat population was formed for efficacy analyses and was
defined as all patients who received at least 1 dose of study
drug. The primary efficacy end points were the ACR20
response rate at week 24, the change in modified total Sharp
scores at week 52, and the change in HAQ scores at week 52.
The analysis for ACR response was nonresponder imputation
(NRI), in which nonresponders were patients who did not
achieve an ACR20 response, who withdrew from the study, or
who received additional traditional DMARD therapy on or
after week 16. The 3 primary efficacy end points were analyzed
in hierarchic order, beginning with the ACR20 response rates,
followed by the modified total Sharp scores, and ending with
HAQ scores. A closed testing procedure was chosen to control
the overall significance level at 0.05. An initial global null
hypothesis was tested for the first hierarchic primary efficacy
end point, the ACR20 response. If this was significant (P ⱕ
0.05), pairwise comparisons between each adalimumab group
and the placebo group would be performed. If all individual
hypothesis tests were significant, then a repeat of the aforementioned testing procedure for the second hierarchic primary
efficacy end point, the modified total Sharp score, would be
done. This was repeated a third time for the HAQ if the
modified Sharp score showed a significant difference.
Tests of normality for the change from baseline in the
total Sharp score and HAQ score were conducted using the
Shapiro-Wilk test. If the data were normal, analysis of covariance (ANCOVA) would be performed. Otherwise, a nonparametric approach (i.e., ranked ANCOVA) would be performed,
with the baseline erosion score or baseline HAQ score as the
covariate. Missing Sharp score values were imputed by linear
extrapolation from baseline and week 24 to week 52. Changes
from baseline to the last observation carried forward in the
mean erosion scores, joint space narrowing scores, HAQ
TREATMENT WITH ADALIMUMAB IN ACTIVE RA
1403
Table 1. Demographic and clinical characteristics at baseline*
Characteristic
Demographics
Age, years
Female, no. (%)
White, no. (%)
Disease duration, years
ACR core set
Tender joint count (0–68 scale)
Swollen joint count (0–66 scale)
Patient’s assessment of pain, mm (0–100-mm VAS)†
Patient’s global assessment of disease activity, mm (0–100-mm VAS)‡
Physician’s global assessment of disease activity, mm (0–100-mm VAS)‡
HAQ score (0–3 scale)§
C-reactive protein, mg/dl (normal ⬍0.8)
Radiographic
Modified total Sharp score (0–398 scale)¶
Erosion score (0–230 scale)¶
Joint space narrowing score (0–168 scale)¶
Rheumatoid factor
Serum concentration, IU/ml (normal ⬍60)
% positive at screening
SF-36 scores (0–100 scale)#
Physical function
Physical role
Body pain
General health
Vitality
Social function
Emotional role
Mental health
DMARD therapy
Weekly MTX dose, mg/kg
Mean
Median
Mean number of previous DMARDs, including MTX
Adalimumab
40 mg every other week
plus MTX
(n ⫽ 207)
Adalimumab
20 mg weekly
plus MTX
(n ⫽ 212)
Placebo
plus MTX
(n ⫽ 200)
56.1 ⫾ 13.5
158 (76.3)
173 (83.6)
11.0 ⫾ 9.2
57.3 ⫾ 10.5
160 (75.5)
181 (85.4)
11.0 ⫾ 9.4
56.1 ⫾ 12.0
146 (73.0)
166 (83.0)
10.9 ⫾ 8.8
27.3 ⫾ 12.7
19.3 ⫾ 9.8
55.9 ⫾ 20.4
52.7 ⫾ 21.0
62.0 ⫾ 16.7
1.45 ⫾ 0.63
1.8 ⫾ 2.3
27.9 ⫾ 13.6
19.6 ⫾ 9.9
55.2 ⫾ 23.0
51.9 ⫾ 23.1
61.6 ⫾ 16.8
1.44 ⫾ 0.64
1.4 ⫾ 1.4
28.1 ⫾ 13.8
19.0 ⫾ 9.5
56.3 ⫾ 22.9
54.3 ⫾ 22.9
61.3 ⫾ 17.3
1.48 ⫾ 0.59
1.8 ⫾ 2.1
72.1 ⫾ 60.7
41.4 ⫾ 33.4
30.7 ⫾ 29.2
66.4 ⫾ 56.3
36.7 ⫾ 31.4
29.7 ⫾ 26.9
66.4 ⫾ 47.4
37.2 ⫾ 25.8
29.2 ⫾ 24.5
272.8 ⫾ 422.1
81.6
309.0 ⫾ 589.4
81.2
457.0 ⫾ 910.1
89.5
38.6 ⫾ 22.6
24.0 ⫾ 35.1
37.0 ⫾ 16.2
50.5 ⫾ 20.0
36.2 ⫾ 20.2
62.9 ⫾ 26.5
60.0 ⫾ 42.7
70.1 ⫾ 18.1
38.0 ⫾ 23.8
23.5 ⫾ 34.5
38.6 ⫾ 17.7
49.4 ⫾ 21.1
37.2 ⫾ 19.8
64.6 ⫾ 25.9
58.3 ⫾ 44.7
70.0 ⫾ 19.9
34.9 ⫾ 21.7
24.4 ⫾ 33.8
37.3 ⫾ 17.4
48.6 ⫾ 20.8
32.6 ⫾ 19.9
61.2 ⫾ 27.1
59.9 ⫾ 44.2
69.1 ⫾ 19.8
16.7 ⫾ 4.5
15.0
2.4
16.3 ⫾ 4.6
15.0
2.4
16.7 ⫾ 4.1
15.0
2.4
* There were no statistically significant differences in any demographic or baseline characteristic between the placebo group and the 2 adalimumab
dosage groups (by Kruskal-Wallis test for continuous variables and Pearson’s chi-square test for discrete variables). Except where indicated
otherwise, values are the mean ⫾ SD. MTX ⫽ methotrexate; ACR ⫽ American College of Rheumatology; VAS ⫽ visual analog scale; HAQ ⫽
Health Assessment Questionnaire; SF-36 ⫽ Medical Outcomes Study Short Form 36-item health survey; DMARDs ⫽ disease-modifying
antirheumatic drugs.
† 0 ⫽ no pain and 100 ⫽ severe pain.
‡ 0 ⫽ no disease activity and 100 ⫽ extreme disease activity.
§ 0 ⫽ no difficulty and 3 ⫽ unable to perform activity.
¶ Greater scores indicate more radiographic evidence of joint damage.
# Greater scores indicate better functioning.
scores, SF-36 scores, and other ACR core criteria were evaluated using ANCOVA, with the baseline value as the covariate.
Pearson’s chi-square test was used to test the differences in
ACR20, ACR50, and ACR70 responses (by NRI) between
treatment groups. Values are reported as the mean ⫾ SD.
RESULTS
Patient characteristics. Among the 795 patients
screened, 619 were randomized to receive 1 of the 3
treatment regimens. Baseline demographic and clinical
characteristics were well balanced across the 3 treatment
groups (Table 1). The patient population had moderate to
severe, long-standing, DMARD-resistant RA. The mean
disease duration was 10.9 years, and mean tender and
swollen joint counts were 27.8 (of 68) and 19.3 (of 66),
respectively. The mean MTX dose was 16.6 mg/week. The
mean modified total Sharp score, erosion score, and joint
space narrowing score was 68.3 (scale 0–398), 38.4 (scale
0–230), and 29.9 (scale 0–168), respectively. There was no
difference in the mean number of previous DMARDs,
1404
KEYSTONE ET AL
placebo (172 of 200) were analyzed. Of the radiographic
findings analyzed, 52-week radiographic data were not
available for 9.8% of the patients in the 40 mg adalimumab group (18 of 183), 6.6% of the patients in the 20
mg adalimumab group (13 of 196), and 6.4% of the
Figure 1. Profile of trial involving treatment with adalimumab (a
human anti–tumor necrosis factor monoclonal antibody) as compared
with placebo in patients with active rheumatoid arthritis receiving
concomitant methotrexate (MTX) therapy.
which included MTX, between adalimumab-treated patients and placebo-treated patients (mean 2.4 for both). A
total of 188 adalimumab-treated patients (44.9%) and 99
placebo-treated patients (49.5%) received oral corticosteroids at some point during the study. In addition, there
were no substantial differences in terms of the types of
previous DMARDs used between each adalimumab group
and the placebo group.
Per protocol, the investigators were advised to
follow the Centers for Disease Control and Prevention
prophylaxis guidelines for the treatment of latent tuberculosis. At baseline, 2.6% of the adalimumab-treated
patients (11 of 419) and 3.5% of the placebo-treated
patients (7 of 200) were PPD positive. Among the
PPD-positive patients, prophylaxis therapy was administered to 5 patients (1.2%) in the adalimumab group and
7 patients (3.5%) in the placebo group; not all of the
PPD-positive patients received prophylaxis, for a variety
of reasons, including prior prophylaxis, possible liver
toxicity, or past BCG vaccination.
Disposition. A total of 467 patients (75.4%)
completed 52 weeks of treatment (Figure 1). Discontinuations occurred in 92 patients (22.0%) in the adalimumab groups and 60 patients (30.0%) in the placebo
group. Twelve adalimumab-treated patients (2.9%) and
23 placebo-treated patients (11.5%) withdrew because
of lack of efficacy. Forty-two adalimumab-treated patients (10.0%) and 13 placebo-treated patients (6.5%)
discontinued treatment because of adverse events.
Radiographic data on 88.4% of patients treated
with adalimumab 40 mg every other week (183 of 207),
92.5% of patients treated with adalimumab 20 mg
weekly (196 of 212), and 86.0% of patients treated with
Figure 2. Changes from baseline to week 52 in the modified total
Sharp radiographic progression scores (extrapolated data) (A), erosion
scores (last observation carried forward [LOCF] data) (B), and joint
space narrowing scores (LOCF data) (C) among the patients receiving
adalimumab 40 mg every other week plus methotrexate (MTX) (■),
adalimumab 20 mg weekly plus MTX (Œ), and placebo plus MTX (E).
ⴱ ⫽ P ⱕ 0.01, † ⫽ P ⱕ 0.001, and ‡ ⫽ P ⱕ 0.05 versus placebo (by
analysis of covariance with the baseline value as the covariate).
TREATMENT WITH ADALIMUMAB IN ACTIVE RA
Figure 3. Distribution of patients who showed improvement in the
American College of Rheumatology (ACR) criteria of at least 20%,
50%, and 70% (A, B, and C, respectively) (using nonresponder
imputation), among the patients receiving adalimumab 40 mg every
other week plus methotrexate (MTX) (■), adalimumab 20 mg weekly
plus MTX (Œ), and placebo plus MTX (E). ⴱ ⫽ P ⱕ 0.001, and † ⫽
P ⱕ 0.01 versus placebo (by Pearson’s chi-square test).
patients in the placebo group (11 of 172); these radiographic data were therefore extrapolated.
Radiographic progression. The rate of radiographic progression was significantly less in the
adalimumab-treated patients compared with the
placebo-treated patients at both 24 weeks and 52 weeks.
1405
Changes from baseline in the mean total Sharp score
among patients treated with adalimumab 40 mg every
other week and those treated with adalimumab 20 mg
weekly were a mean ⫾ SD 0.1 ⫾ 4.8 and 0.8 ⫾ 4.9,
respectively, at week 52 versus 2.7 ⫾ 6.8 among patients
receiving placebo (Figure 2A) (P ⱕ 0.001 for each
comparison). The differences between the group treated
with adalimumab 40 mg every other week and the group
treated with adalimumab 20 mg weekly were not significant at weeks 24 or 52.
There were statistically significantly fewer joint
erosions in the adalimumab-treated patients than in the
placebo-treated patients (Figure 2B). The changes in the
mean erosion scores at week 52 following treatment with
adalimumab 40 mg every other week and 20 mg weekly
were a mean ⫾ SD 0.0 ⫾ 2.8 and 0.4 ⫾ 2.5, respectively,
versus a change in the mean erosion score of the placebo
group of 1.6 ⫾ 4.4 (P ⱕ 0.001 for each comparison). At
week 52, no new erosions were observed in significantly
more patients taking adalimumab, either 40 mg every
other week (61.8%) or 20 mg weekly (57.9%), as compared with patients taking placebo (46.0%) (P ⱕ 0.01
and P ⱕ 0.05, respectively). Similarly, improved erosion
scores (i.e., scores ⬍0) were observed in significantly
more patients taking adalimumab, either 40 mg every
other week (38.2%) or 20 mg weekly (29.5%), as compared with patients taking placebo (19.3%) (P ⱕ 0.001
and P ⱕ 0.05, respectively).
Compared with the effects of placebo, adalimumab attenuated the rate of joint space narrowing
(Figure 2C). The mean change in the joint space narrowing score at week 52 was statistically significantly
lower among patients treated with adalimumab 40 mg
every other week (mean ⫾ SD 0.1 ⫾ 2.3) than among
those taking placebo (1.0 ⫾ 3.0) (P ⱕ 0.01). Significantly
more patients treated with adalimumab, either 40 mg
every other week (68.5%) or 20 mg weekly (67.8%), as
compared with patients taking placebo (52.2%) demonstrated improvement or no change in joint space narrowing at week 52 (P ⱕ 0.01).
Signs and symptoms. Patients treated with either
regimen of adalimumab demonstrated rapid, statistically
significant, and sustained clinical improvements compared with those treated with placebo, as measured by
the ACR response criteria. The ACR20, ACR50, and
ACR70 response rates in both adalimumab groups
showed a distinct separation from those in the placebo
group by week 2, with this treatment effect persisting
through week 52 (Figures 3A, B, and C, respectively).
Adalimumab-treated patients exhibited a response
quickly, with more patients achieving an ACR20 re-
1406
KEYSTONE ET AL
Table 2.
Patients with at least 20%, 50%, and 70% improvement in the ACR response criteria*
ACR response*
ACR20 response
Week 24
Week 52
ACR50 response
Week 24
Week 52
ACR70 response
Week 24
Week 52
Adalimumab
40 mg every other week
plus MTX
(n ⫽ 207)
Adalimumab
20 mg weekly
plus MTX
(n ⫽ 212)
Placebo
plus MTX
(n ⫽ 200)
131 (63.3)†
122 (58.9)†
129 (60.8)†
116 (54.7)†
59 (29.5)
48 (24.0)
81 (39.1)†
86 (41.5)†
87 (41.0)†
80 (37.7)†
19 (9.5)
19 (9.5)
43 (20.8)†
48 (23.2)†
37 (17.5)†
44 (20.8)†
5 (2.5)
9 (4.5)
* Values are the number (%) of patients. All patients who withdrew from the study or received additional
DMARD therapy were considered nonresponders. See Table 1 for definitions.
† P ⱕ 0.001 versus placebo (by Pearson’s chi-square test).
sponse at week 2 (the first evaluation) than at any other
time point. At week 2, an ACR20 response was achieved
by 25.6% and 32.5% of patients treated with adalimumab 40 mg every other week and 20 mg weekly,
respectively, versus 13.0% of patients taking placebo
(P ⱕ 0.001 for each comparison) (Figure 3A). At weeks
24 and 52, ACR20, ACR50, and ACR70 response rates
were statistically significantly greater with either of the
adalimumab regimens than with placebo (P ⱕ 0.001)
(Table 2). Furthermore, each adalimumab group was
associated with statistically significant improvements in
each ACR core component compared with the changes
in the placebo group at weeks 24 and 52 (P ⱕ 0.001)
(Table 3). In both adalimumab treatment groups, the
C-reactive protein (CRP) concentrations decreased to
normal or near-normal levels by week 24 and remained
stable to week 52, whereas in the placebo group, CRP
concentrations remained elevated at twice the normal
range at week 52.
Moreover, at week 52, the number of patients
requiring additional DMARD therapy was significantly
lower among patients treated with adalimumab 40 mg
every other week (n ⫽ 9) or adalimumab 20 mg weekly
(n ⫽ 6) than among those receiving placebo (n ⫽ 33)
(P ⬍ 0.001). The difference in the number requiring
additional DMARDs between the group treated with
adalimumab 40 mg every other week and the group
treated with adalimumab 20 mg weekly was not statistically significant.
Physical function and health-related quality of
life. At week 52, improvements (decreases from baseline)
in the mean HAQ physical function scores were statistically
significantly greater for those receiving adalimumab 40 mg
every other week (mean ⫾ SD ⫺0.59 ⫾ 0.57) or adali-
mumab 20 mg weekly (⫺0.61 ⫾ 0.55) than for those
receiving placebo (⫺0.25 ⫾ 0.56) (P ⱕ 0.001 for each
comparison) (Table 3). Improvements in the mean HAQ
scores following treatment with either adalimumab regimen were statistically significantly greater than those seen
in the placebo group at all time points, including the first
scheduled study visit at week 2 (mean ⫾ SD ⫺0.29 ⫾ 0.39
for adalimumab 40 mg every other week and ⫺0.28 ⫾ 0.41
for adalimumab 20 mg weekly compared with ⫺0.12 ⫾
0.37 for placebo; P ⱕ 0.001 for each comparison) (Figure
4). A 0.22-unit decrease in HAQ scores has been associated with meaningful clinical improvements and can be
considered to represent the minimum clinically important
difference (MCID) (18).
At week 52, improvements (increases from baseline) in the mean SF-36 scores were statistically significantly greater for 7 of 8 domains following treatment
with adalimumab 40 mg every other week and were
greater for all 8 domains with adalimumab 20 mg weekly
as compared with placebo (Figure 5). Increases of 5–10
points in individual SF-36 domain scores have been
associated with meaningful clinical improvements and
can be considered to represent MCIDs (19). At week 52,
treatment with adalimumab 40 mg every other week
resulted in at least a 10-point improvement in 5 of the 8
SF-36 domains (physical function, physical role, body
pain, vitality, and social function). Moreover, treatment
with adalimumab 20 mg weekly resulted in at least a
10-point improvement in 7 of the 8 domains (physical
function, physical role, body pain, general health, vitality, social function, and emotional role). In contrast, the
placebo group achieved at least a 10-point improvement
in only 1 of 8 SF-36 domains (physical role).
TREATMENT WITH ADALIMUMAB IN ACTIVE RA
1407
Table 3. Changes in ACR core component criteria at week 24 and week 52*
Core set evaluation measure
Tender joint count (0–68 scale)
Mean baseline value
Week 24 absolute change
Week 24 percent change
Week 52 absolute change
Week 52 percent change
Swollen joint count (0–66 scale)
Mean baseline value
Week 24 absolute change
Week 24 percent change
Week 52 absolute change
Week 52 percent change
Patient’s assessment of pain, mm (0–100-mm VAS)‡
Mean baseline value
Week 24 absolute change
Week 24 percent change
Week 52 absolute change
Week 52 percent change
Patient’s global assessment of disease activity, mm (0–100-mm VAS)§
Mean baseline value
Week 24 absolute change
Week 24 percent change
Week 52 absolute change
Week 52 percent change
Physician’s global assessment of disease activity, mm (0–100-mm VAS)§
Mean baseline value
Week 24 absolute change
Week 24 percent change
Week 52 absolute change
Week 52 percent change
HAQ score (0–3 scale)¶
Mean baseline value
Week 24 absolute change
Week 24 percent change
Week 52 absolute change
Week 52 percent change
C-reactive protein, mg/dl (normal ⬍0.8)
Mean baseline value
Week 24 absolute change
Week 24 percent change
Week 52 absolute change
Week 52 percent change
Adalimumab
40 mg every other week
plus MTX
(n ⫽ 207)
Adalimumab
20 mg weekly
plus MTX
(n ⫽ 212)
Placebo
plus MTX
(n ⫽ 200)
27.3 ⫾ 12.7
⫺15.4 ⫾ 12.3†
⫺56.4
⫺16.6 ⫾ 12.8†
⫺60.8
27.9 ⫾ 13.6
⫺16.6 ⫾ 12.0†
⫺59.5
⫺16.8 ⫾ 13.8†
⫺60.2
28.1 ⫾ 13.8
⫺9.3 ⫾ 14.4
⫺33.1
⫺9.6 ⫾ 14.7
⫺34.5
19.3 ⫾ 9.8
⫺11.1 ⫾ 9.7†
⫺57.5
⫺11.9 ⫾ 11.0†
⫺61.7
19.6 ⫾ 9.9
⫺11.7 ⫾ 9.8†
⫺59.7
⫺11.7 ⫾ 10.9†
⫺59.7
19.0 ⫾ 9.5
⫺5.9 ⫾ 10.6
⫺31.1
⫺5.6 ⫾ 10.3
⫺29.5
55.9 ⫾ 20.4
⫺28.2 ⫾ 25.8†
⫺50.4
⫺29.4 ⫾ 26.4†
⫺52.6
55.2 ⫾ 23.0
⫺27.9 ⫾ 27.0†
⫺50.5
⫺27.4 ⫾ 28.5†
⫺49.6
56.3 ⫾ 22.9
⫺12.6 ⫾ 26.1
⫺22.4
⫺11.2 ⫾ 27.7
⫺19.9
52.7 ⫾ 21.0
⫺27.2 ⫾ 26.9†
⫺51.6
⫺27.5 ⫾ 28.4†
⫺52.2
51.9 ⫾ 23.1
⫺24.7 ⫾ 27.2†
⫺47.6
⫺24.1 ⫾ 28.4†
⫺46.4
54.3 ⫾ 22.9
⫺11.4 ⫾ 28.1
⫺21.0
⫺10.9 ⫾ 30.4
⫺20.1
62.0 ⫾ 16.7
⫺37.3 ⫾ 21.6†
⫺60.2
⫺39.4 ⫾ 22.2†
⫺63.5
61.6 ⫾ 16.8
⫺36.3 ⫾ 24.1†
⫺58.9
⫺36.2 ⫾ 24.4†
⫺58.8
61.3 ⫾ 17.3
⫺21.1 ⫾ 25.3
⫺34.4
⫺19.5 ⫾ 25.8
⫺31.8
1.45 ⫾ 0.63
⫺0.56 ⫾ 0.52†
⫺38.6
⫺0.59 ⫾ 0.57†
⫺40.7
1.44 ⫾ 0.64
⫺0.60 ⫾ 0.53†
⫺41.7
⫺0.61 ⫾ 0.55†
⫺42.4
1.48 ⫾ 0.59
⫺0.24 ⫾ 0.52
⫺16.2
⫺0.25 ⫾ 0.56
⫺16.9
1.8 ⫾ 2.3
⫺1.0 ⫾ 2.9†
⫺55.6
⫺0.7 ⫾ 1.4†
⫺38.9
1.4 ⫾ 1.4
⫺0.8 ⫾ 1.3†
⫺57.1
⫺0.7 ⫾ 1.4†
⫺50.0
1.8 ⫾ 2.1
⫺0.2 ⫾ 1.9
⫺11.1
⫺0.1 ⫾ 1.9
⫺5.6
* Except where indicated otherwise, values are the mean ⫾ SD, based on the last observation carried forward to week 24 or week 52. A negative
mean change indicates an improvement in that ACR criterion. See Table 1 for definitions.
† P ⱕ 0.001 versus placebo (by analysis of covariance with the baseline value as the covariate).
‡ 0 ⫽ no pain and 100 ⫽ severe pain.
§ 0 ⫽ no disease activity and 100 ⫽ extreme disease activity.
¶ 0 ⫽ no difficulty and 3 ⫽ unable to perform activity.
Adverse events. Adalimumab was generally well
tolerated. Because a higher proportion of the placebotreated patients discontinued the study compared with
the adalimumab-treated patients (30% versus 22%) and
the mean duration of treatment in the placebo arm was
shorter than that in the adalimumab arm (268 days
versus 313 days), adverse events were analyzed both by
the proportion of patients experiencing an event and by
the rate (expressed as number of patients per patientyear) of those events.
The overall frequencies and rates of serious
adverse events were similar among the adalimumabtreated patients (n ⫽ 60: 14.3% reporting serious adverse events [0.16 patients/patient-year]). However, the
proportion of patients reporting serious infections (requiring hospitalization or intravenous antibiotics) was
1408
Figure 4. Changes in the Health Assessment Questionnaire (HAQ)
scores (last observation carried forward data) among the patients
receiving adalimumab 40 mg every other week plus methotrexate
(MTX) (■), adalimumab 20 mg weekly plus MTX (Œ), and placebo
plus MTX (E). ⴱ ⫽ P ⱕ 0.001 versus placebo (by analysis of covariance
with the baseline value as the covariate).
significantly greater with adalimumab (16 of 419, or
3.8%) than with placebo (1 of 200, or 0.5%) (P ⱕ 0.02).
Serious infections were reported by significantly more
patients treated with adalimumab 40 mg every other
week (11 of 207, or 5.3%) than with placebo (P ⱕ 0.01),
but there was no statistically significant difference between the group receiving adalimumab 20 mg weekly (5
of 212, or 2.4%) as compared with placebo. Adjusting
for exposure time, serious infections occurred at a rate
of 0.06 patients/patient-year with adalimumab 40 mg
every other week, 0.03 patients/patient-year with adalimumab 20 mg weekly, and 0.01 patients/patient-year
with placebo.
One patient treated with adalimumab 40 mg
every other week was diagnosed as having primary
tuberculosis of the cervical lymph nodes, and was with-
Figure 5. Changes in the Medical Outcomes Study Short Form 36item health survey (SF-36) scores (last observation carried forward
data). ⴱ ⫽ P ⱕ 0.05 versus placebo (by analysis of covariance with the
baseline value as the covariate). MTX ⫽ methotrexate.
KEYSTONE ET AL
drawn from the study and successfully treated. At baseline, this patient had a negative PPD test result and a
normal chest radiograph. One patient treated with adalimumab 40 mg every other week plus MTX was diagnosed with histoplasmosis infection after 78 days of
treatment, and was subsequently withdrawn from the
study and successfully treated with antifungal therapy.
This patient lived in an area that was endemic for
histoplasmosis infection. One patient treated with adalimumab 40 mg every other week was diagnosed as having
herpes zoster and developed encephalitis, which resolved but resulted in mild lower extremity weakness.
Four adalimumab-treated patients developed non-skin
cancers, including non-Hodgkin’s lymphoma, adenocarcinoma, testicular seminoma, and breast cancer. One
patient treated with adalimumab 20 mg weekly was
diagnosed as having worsening of a central demyelinating illness. This patient had experienced an episode of
paresthesia 18 years earlier and developed the latest
episode 1 month after starting therapy. There were 2
deaths (1 related to multiple fractures and 1 related to
urosepsis) in the group receiving adalimumab 40 mg
every other week, 1 death (related to complications from
chemotherapy for the treatment of lymphoma) in the
group receiving adalimumab 20 mg weekly, and no
deaths in the placebo group.
Overall, similar proportions of adalimumabtreated patients (n ⫽ 391, or 93.3%) and placebotreated patients (n ⫽ 181, or 90.5%) reported at least 1
adverse event. Moreover, the rate of adverse events was
similar between the adalimumab-treated patients (1.07
patients/patient-year) and the placebo-treated patients
(1.12 patients/patient-year).
The most frequently reported adverse events
(occurring in ⱖ10% of patients) are presented in Table
4. Injection-site reaction (defined as localized erythema,
itching, hemorrhage, pain, or swelling) was the most
commonly reported adverse event and was observed in
similar proportions of adalimumab- and placebo-treated
patients (24.1% and 24.0%, respectively). The primary
injection-site reaction was injection-site pain, which was
reported by 17.7% of the combined adalimumab group
and 22.0% of the placebo group. Injection-site reactions
consisting of localized erythema, itching, or swelling
occurred in 6.2% of the adalimumab group and 3.0% of
the placebo group (P ⫽ 0.10). Most injection-site reactions were mild or moderate in nature.
Adalimumab therapy was also associated with
statistically significant decreases (P ⱕ 0.05 compared
with baseline values) in the mean white blood cell count,
platelet count, and neutrophil percentage, as well as
TREATMENT WITH ADALIMUMAB IN ACTIVE RA
1409
Table 4. Adverse events*
Adalimumab 40 mg
every other week plus MTX
(179.2 patient-years)
(n ⫽ 207)
Adverse event
Injection-site reaction†
Upper respiratory tract
infection
Rhinitis
Sinusitis
Accidental injury
Headache
Infection
Nausea
Diarrhea
Arthralgia
Rash‡
Joint disorder
Clinical-flare reaction
Adalimumab 20 mg
weekly plus MTX
(186.7 patient-years)
(n ⫽ 212)
Placebo plus MTX
(161.3 patient-years)
(n ⫽ 200)
No. (%)
No./patient-year
No. (%)
No./patient-year
No. (%)
No./patient-year
54 (26.1)
41 (19.8)
0.30
0.23
47 (22.2)
41 (19.3)
0.25
0.22
48 (24.0)
27 (13.5)
0.30
0.17
34 (16.4)
33 (15.9)
29 (14.0)
26 (12.6)
15 (7.2)
19 (9.2)
19 (9.2)
14 (6.8)
22 (10.6)
13 (6.3)
12 (5.8)
0.19
0.18
0.16
0.15
0.08
0.11
0.11
0.08
0.12
0.07
0.07
37 (17.5)
31 (14.6)
28 (13.2)
29 (13.7)
33 (15.6)
26 (12.3)
24 (11.3)
29 (13.7)
20 (9.4)
14 (6.6)
8 (3.8)
0.20
0.17
0.15
0.16
0.18
0.14
0.13
0.16
0.11
0.08
0.04
33 (16.5)
26 (13.0)
24 (12.0)
12 (6.0)
9 (4.5)
25 (12.5)
30 (15.0)
24 (12.0)
15 (7.5)
23 (11.5)
29 (14.5)
0.21
0.16
0.15
0.07
0.06
0.16
0.19
0.15
0.09
0.14
0.18
* Adverse events occurring in ⱖ10% of patients in any treatment group. MTX ⫽ methotrexate.
† Erythema and/or itching, hemorrhage, pain, or swelling at the site of injection.
‡ At site other than injection site.
statistically significant increases (P ⱕ 0.05 compared
with baseline values) in the mean hemoglobin concentration, hematocrit, and lymphocyte percentage (data
not shown), with all of these indices moving toward
more normal values. In the placebo group, changes in all
of these parameters were of less magnitude and were not
statistically significant for the platelet count and lymphocyte percentage.
At week 52, 12.1% of adalimumab-treated patients (48 of 397) and 9.1% of placebo-treated patients
(17 of 186) converted from ANA negative to ANA
positive (titer ⱖ1:80), and 5.5% of adalimumab-treated
patients (22 of 397) and 5.9% of placebo-treated patients (11 of 186) converted from ANA positive to ANA
negative. Among patients who had an increased ANA
titer at baseline (any increase in titer), anti-dsDNA
antibodies were detected in 11.7% of the adalimumabtreated patients (14 of 120) and in none of the placebotreated patients at week 52. No patients developed
symptoms of lupus-like illness. Two patients in the group
receiving adalimumab 40 mg every other week, 1 patient
in the group receiving adalimumab 20 mg weekly, and 1
patient in the placebo group were positive for antiadalimumab antibodies on at least 1 occasion. The assay
was performed repeatedly during the treatment period
(from the first dose to up to 30 days after the last dose).
DISCUSSION
This multicenter, placebo-controlled, 52-week trial
demonstrated that adding adalimumab (40 mg every other
week or 20 mg weekly subcutaneously) to MTX in patients
with active RA provided significant radiographic, clinical,
and functional benefits compared with MTX alone. Patients in this study had moderate to severe, long-standing
RA that was partially responsive to MTX and were at
increased risk of radiographic disease progression. Benefits
with the adalimumab plus MTX combination were
achieved quickly and were sustained over 52 weeks.
Both adalimumab regimens inhibited the rate of
radiographic disease progression. Modified total Sharp
scores increased more with MTX alone than with adalimumab plus MTX after both 24 weeks and 52 weeks of
treatment. The therapeutic effect of adalimumab was
statistically significant even when erosion scores and
joint space narrowing scores were analyzed independently. Such results suggest that adalimumab influences
different disease manifestations, including joint erosions
and joint space narrowing. These results are consistent
with the recognized ability of TNF to induce bone
resorption (20) and inhibit the synthesis of proteoglycans by cartilage (21). Prevention of further joint damage, as assessed by inhibition of the rate of radiographic
disease progression, represents an important therapeutic
goal in RA because joint damage strongly correlates
with functional deterioration, particularly late in the
disease course (22,23).
The rate of increase in the total modified Sharp
score in the placebo group during this trial was less than
the expected linear progression calculated from the
baseline total Sharp score divided by disease duration.
1410
Interventions (e.g., DMARDs, corticosteroids) used
prior to the study and MTX and corticosteroids used
during the study have been shown to change the rate of
increase in radiographic progression. This is one explanation for this finding.
In addition to radiographic benefits, clinical and
functional improvements were robust and sustained up
to 52 weeks with both adalimumab regimens. The magnitude of the responses with adalimumab therapy was
substantial for such a study population. ACR responses
with adalimumab were rapid, with the greatest number
of patients responding for the first time at week 2 (the
first followup study visit). Moreover, fewer patients
treated with adalimumab required the use of rescue
DMARDs than did patients treated with placebo.
Improvements were observed in patient-reported
evaluations (HAQ and SF-36), indicating that adalimumab therapy positively impacts patients’ ability to
perform physical activities necessary for daily living and
health-related quality of life. Remarkably, HAQ scores
demonstrated statistically and clinically significant improvement in as little as 2 weeks. During adalimumab
treatment, white blood cell counts, platelet counts, and
neutrophil percentages decreased, whereas hemoglobin
concentrations, hematocrit, and lymphocyte percentages
increased, possibly because of the antiinflammatory
effect of adalimumab.
The overall incidence of adverse events was similar in the adalimumab and placebo groups, and most
adverse events were mild or moderate. However, serious
infections occurred significantly more often with adalimumab (3.8%) than with placebo (0.5%) (P ⱕ 0.02).
Serious infection is a risk associated with TNF antagonists (24). It is recommended that administration of
these agents be discontinued in patients who develop a
serious infection. The rate of serious infections among
adalimumab-treated patients in this 52-week study was
comparable with the estimated yearly rate of serious
infections among patients with RA (0.031–0.096/patientyear) (25,26) and comparable with those reported from
the safety databases for the 2 currently marketed TNF
antagonists, etanercept (0.048/patient-year) (27) and
infliximab (6%) (28). The incidence of non-skin cancers
among adalimumab-treated patients in this study was
similar to that expected of the age- and sex-matched
general population, based on the Surveillance, Epidemiology, End Result (SEER) database of the National
Cancer Institute (29,30). As has been observed with
other TNF antagonists, adalimumab treatment was associated with a higher rate of development of ANAs and
KEYSTONE ET AL
anti-dsDNA antibodies, but no cases of lupus or lupuslike illness were observed in this study.
Several combination regimens have been demonstrated to be effective in RA patients who exhibit a
partial response to MTX, including combinations of
MTX with traditional DMARDs (cyclosporine, sulfasalazine, hydroxychloroquine, or leflunomide) or biologic DMARDs (infliximab, etanercept, or anakinra)
(31). Based on the results presented here, we conclude
that addition of adalimumab (40 mg every other week or
20 mg weekly administered subcutaneously) to the MTX
regimen in patients partially responsive to MTX provides additional benefit, with inhibition of the progression of structural joint damage, reduction in the signs
and symptoms, and improvement in physical function
and health-related quality of life.
ACKNOWLEDGMENTS
The authors wish to thank the following principal
investigators and their study coordinators: James Anderson,
MD, Wichita, KS; Andrew Baldassare, MD, St. Louis, MO;
Herbert Baraf, MD, Wheaton, MD; Mary Bell, MD, Toronto,
Ontario, Canada; Barry Bockow, Seattle, WA; Arthur Bookman, MD, Toronto, Ontario, Canada; Michael Borofskyl, MD,
West Reading, PA; Richard Brasington, Jr, MD, St. Louis,
MO; Michael Burnette, MD, Tampa, FL; Walter Chmelewski,
MD, Raleigh, NC; Paul F. Dellaripa, MD, Burlington, MA;
Gino DiVittorio, MD, Mobile, AL; William Edwards, MD,
Charleston, SC; Ronald Emkey, MD, Wyomissing, PA; John
Ervin, MD, Kansas City, MO; Robert Ettlinger, MD, Tacoma,
WA; Pam Freeman, MD, Orlando, FL; Norman Gaylis, MD,
Aventura, FL; Perri Ginder, MD, Shawnee Mission, KS; Alben
Goldstein, MD, Falls Church, VA; Maria Greenwald, Rancho
Mirage, CA; Dale Halter, MD, Houston, TX; John Hanly,
MD, Halifax, Nova Scotia, Canada; Robert Harrell, MD,
Durham, NC; Paul Howard, MD, Paradise Valley, AZ; Adrian
Jaffer, MD, La Jolla, CA; Howard Kenney, MD, Spokane,
WA; Brian Keroack, MD, Portland, ME; Alan Kivitz, MD,
Duncansville, PA; Steven Klein, MD, Cumberland, MD; Elliot
Kopp, MD, Raleigh, NC; Richard Lautzenheiser, MD, Indianapolis, IN; Robert Levin, MD, Clearwater, FL; George Liang,
MD, Chicago, IL; William Maier, MD, Eugene, OR; David
Mandel, MD, Mayfield Village, OH; Howard Marker, MD,
Memphis, TN; William Martin, MD, Calgary, Alberta, Canada; James McMillen, MD, Mechanicsburg, PA; Kenneth
Miller, MD, Danbury, CT; Brent Mohr, MD, South Bend, IN;
Robert Moidel, MD, Sellersville, PA; Steen Mortensen, MD,
Wichita, KS; Carter Multz, MD, San Jose, CA; Jeffrey Neal,
MD, Lexington, KY; Daniel Norden, MD, Norristown, PA;
Robert Offer, MD, Penticton, British Columbia, Canada;
William Palmer, MD, Omaha, NE; Bryan Pogue, MD, Boise,
ID; Ron Pruitt, MD, Nashville, TN; Lee Rocamora, MD,
Winston-Salem, NC; Sanford Roth, MD, Phoenix, AZ; Marshall Sack, MD, Austin, TX; Bruce Samuels, MD, Dover, NH;
Craig Scoville, MD, Idaho Falls, ID; Gordon Senter, MD,
Salisbury, NC; William Shergy, MD, Huntsville, AL; Tammi
TREATMENT WITH ADALIMUMAB IN ACTIVE RA
Shlotzhauer, MD, Rochester, NY; Kam Shojania, MD, Richmond, British Columbia, Canada; David Sikes, MD,
Zephyrhills, FL; Sheldon Solomon, MD, Voorhees, NJ; James
Speiser, MD, St. Louis, MO; Angela Stupi, MD, Pittsburgh,
PA; Timothy Swartz, MD, Kalamazoo, MI; Elizabeth TaylorAlbert, MD, Oklahoma City, OK; Glen Thomson, MD, Winnipeg, Manitoba, Canada; J. Carter Thorne, MD, Newmarket,
Ontario, Canada; Robert Trapp, MD, Springfield, IL; James
Trice, MD, Concord, NH; Howard Uhl, MD, Grand Rapids,
MI; Charles Weidmann, Van Nuys, CA; Frank Wellborne,
MD, Houston, TX; Christopher Wise, MD, Richmond, VA;
Carol Young, MD, Escondido, CA; and Thomas Zizic, MD,
Baltimore, MD.
The authors also wish to thank all of the patients who
participated and completed the evaluations in the setting of
their severe RA.
1411
13.
14.
15.
16.
17.
18.
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